DESCRIPTION: (provided by the applicant) Uterine leiomyoma is the most common gynecologic neoplasm and the major cause of hysterectomy in reproductive age women. Additionally, these tumors negatively impact reproductive function in women by contributing to infertility and complications of pregnancy. Little is known about the etiology of leiomyoma or the potential impact of environmental agents on the course of this disease. The goal of our research is to understand the etiology of uterine leiomyoma at the molecular level and to elucidate the molecular mechanisms by which exposure to endocrine disruptors may impact the development of these tumors. In Specific Aim 1, we will determine if loss of Tsc-2 tumor suppressor gene/tuberin function and subsequent overexpression of HMGI-C is an alternative pathway for development of leiomyoma. In Specific Aim 2, we will test the hypothesis that loss of tuberin is directly responsible for overexpression of HMGI-C and results in modulation of hormone responsiveness in tuberin deficient cells. Finally in Specific Aim 3, we will determine if the prepubertal period is a window of susceptibility for exposure to environmental xenoestrogens and determine at the molecular level whether this exposure impacts the expression of genes that may contribute to the development of leiomyoma. These experiments will yield new insights into the molecular mechanisms responsible for the altered responsiveness of uterine leiomyomas to endogenous and exogenous hormones and increase our understanding of the potential mechanisms by which exposure to endocrine disruptors could contribute to the development of this disease.